Two functionally distinct amyloid-β intermediates link aggregation pathways to pathology in Alzheimer's disease
- 1University of Sheffield
Abstract
Neurotoxic intermediates formed during amyloid-{beta}(A{beta}) aggregation are thought to drive Alzheimer's disease, yet their rarity and transient nature have obscured their identity and formation pathways in the human brain. Here, we combine super-resolution microscopy and single-molecule functional imaging with kinetic modelling to classify A{beta} intermediates according to their membrane-disrupting activity and connect their damaging effects to the aggregation pathways that generate them. Applying this framework to recombinant A{beta}42, an Alzheimer's knock-in mouse model and human Alzheimer's brain tissue, we find two functionally distinct intermediate populations present across all systems. They form through separate aggregation routes and differ in their neurotoxicity, abundance and susceptibility to inhibition. Both damage neurons and glia, but only one converts into plaques. Suppressing these intermediates pharmacologically in mice reduces plaque burden, attenuates astrogliosis and improves cognition. Our findings connect model systems with human pathology and identify intermediate formation pathways as actionable therapeutic targets across protein-misfolding disorders.
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BibTeX
@misc{urbanek2026functionally,
title = {{Two functionally distinct amyloid-β intermediates link aggregation pathways to pathology in Alzheimer's disease}},
author = {A. Urbanek and A. J. Dear and D. P. Rhodes and E. F. Garland and H. E. Wareing and H. J. Baker and W. Molenkamp and R. Zhang and G. Chen and A. Abelein and S. M. Bell and J. A. Varela and T. Michaels and J. R. Highley and G. Meisl and J. Johansson and S. De},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.26.754651},
url = {https://www.biorxiv.org/content/10.64898/2026.09.26.754651v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Two functionally distinct amyloid-β intermediates link aggregation pathways to pathology in Alzheimer's disease
AU - A. Urbanek
AU - A. J. Dear
AU - D. P. Rhodes
AU - E. F. Garland
AU - H. E. Wareing
AU - H. J. Baker
AU - W. Molenkamp
AU - R. Zhang
AU - G. Chen
AU - A. Abelein
AU - S. M. Bell
AU - J. A. Varela
AU - T. Michaels
AU - J. R. Highley
AU - G. Meisl
AU - J. Johansson
AU - S. De
PY - 2026
DA - 2026/09/26
PB - bioRxiv
DO - 10.64898/2026.09.26.754651
UR - https://www.biorxiv.org/content/10.64898/2026.09.26.754651v1
AB - Neurotoxic intermediates formed during amyloid-{beta}(A{beta}) aggregation are thought to drive Alzheimer's disease, yet their rarity and transient nature have obscured their identity and formation pathways in the human brain. Here, we combine super-resolution microscopy and single-molecule functional imaging with kinetic modelling to classify A{beta} intermediates according to their membrane-disrupting activity and connect their damaging effects to the aggregation pathways that generate them. Applying this framework to recombinant A{beta}42, an Alzheimer's knock-in mouse model and human Alzheimer's brain tissue, we find two functionally distinct intermediate populations present across all systems. They form through separate aggregation routes and differ in their neurotoxicity, abundance and susceptibility to inhibition. Both damage neurons and glia, but only one converts into plaques. Suppressing these intermediates pharmacologically in mice reduces plaque burden, attenuates astrogliosis and improves cognition. Our findings connect model systems with human pathology and identify intermediate formation pathways as actionable therapeutic targets across protein-misfolding disorders.
ER -